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Contribution of Age, Brain Region, Mood Disorder Pathology, and Interindividual Factors on the Methylome of Human Microglia

ABSTRACT: Total of 56 microglia samples from postmortem brain tissue of four different brain regions, medial frontal gyrus (MFG), superior temporal gyrus (STG), subventricular zone (SVZ) and thalamus (THA), of 22 donors, encompassing 1 patient with schizophrenia, 13 patients with mood disorder pathology, and 8 control subjects, were isolated and assayed using a genome-wide methylation array to characterize the DNA methylation landscape of human microglia and the factors that contribute to variations in the microglia methylome

ORGANISM(S): Homo sapiens

PROVIDER: GSE191200 | GEO | 2022/01/31

REPOSITORIES: GEO

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Project description:Despite the well-established role of the frontal and posterior peri-sylvian cortices in many facets of human-cognitive specializations, including language, little is known about the developmental patterning of these regions in human brain. We performed a genome-wide analysis of human cerebral patterning during mid-gestation, a critical epoch in cortical regionalization. A total of 345 genes were identified as differentially expressed (DE) between superior temporal gyrus (STG) and the remaining cerebral cortex (CTX). GO categories representing transcription factors were enriched in STG, while cell-adhesion and extracellular matrix molecules, were enriched in the other cortical regions. Q-PCR or in situ hybridization were performed to validate differential expression in a subset of 32 genes, most of which were confirmed. LIM domain binding 1 (LDB1), which we show to be enriched in the STG, is a recently identified interactor of LIM domain only 4 (LMO4), a gene known to be involved in the asymmetric pattering of the peri-sylvian region in the developing human brain. Protocadherin 17 (PCDH17), a neuronal cell adhesion molecule, was highly enriched in focal regions of the human prefrontal cortex. Contactin Associated Protein-Like 2 (CNTNAP2), in which mutations are known to cause autism, epilepsy and language delay, showed a remarkable pattern of anterior enriched expression in cortical regions important for human higher cognition. Importantly, a similar pattern was not observed in the mouse or rat. These data highlight the importance of expression analysis of human brain and the utility of cross-species comparisons of gene expression. Genes identified here provide a foundation for understanding molecular aspects of human-cognitive specializations and disorders that disrupt them. Experiment Overall Design: Fresh frozen human mid-gestation brains were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders (University of Maryland, Baltimore, MD). After separation of the two hemispheres, tissue from STG was extracted. RNA from STG and remaining CTX was hybridized on both Agilent G4110A arrays (n=8) and Affymetrix HGU133A arrays (n=17).

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Contribution of Age, Brain Region, Mood Disorder Pathology, and Interindividual Factors on the Methylome of Human Microglia

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